Method and composition for enhancement of male erectile function

ABSTRACT

A pharmaceutical composition for enhancing male erectile function comprising an erectile function-enhancing amount of an insulin-like growth factor selected from the group consisting of IGF-1 (Somatmedin-C) and analogue LR3 IGF1 in admixture with a pharmaceutically-acceptable diluents or carrier. Such compositions optionally further comprise compounds selected from an androgen, particularly, testosterone and dihydrotestosterone, a vasodilator, PDE5 inhibitor and prostaglandin E1.

FIELD OF THE INVENTION

The invention relates to methods and compositions for enhancing maleerectile function, particularly using Somatomedins insulin-like growthfactors.

BACKGROUND OF THE INVENTION

Erectile dysfunction (ED) is defined as the inability to achieve andmaintain a penile erection adequate for sexual intercourse. This may bea relative term wherein the frequency of occurrences in which a patientis able to achieve and maintain a penile erection adequate for sexualintercourse has decreased over time as a part of natural aging which issuperimposed with other internal and external factors that impactnegatively upon the natural sexual responses of males. It is a malehealth problem which in its most severe form has been estimated toaffect about 150 million men worldwide. But in North America it isestimated that by the age of 40 years, approximately 25% of men arehaving problems with achieving and sustaining an erection, and thisprobably increases to over 50% for men over 60 years of age.

Impotence generally refers to a severe form of male erectile dysfunctionand is defined as the general inability to achieve and sustain anerection sufficient for intercourse. Erectile function naturallydeclines with age and like the aging process, the decline in erectilefunction experienced by men as they age is a complex biologicalphenomena that results from complicated interactions betweenpsychological, emotional, spiritual and physical factors. Some of thephysical factors include genetics, diet, nutrition, environmentalexposures to toxins, radiation, hormonal factors such as thyroid,adrenal, gonadal, and growth hormones among others: as well as effectsfrom medications and other iatrogenic effects of medical treatments.These are only some of the various factors that may contribute tonatural diseases that combine with aging to cause declining sexualfunction in men and women.

The complexity of the body makes the diagnosis and treatment of EDimprecise. The hormonal issues are rarely considered in diagnosticworkups. For example, the assessment of thyroid, adrenal and growthhormones are not part of the usual diagnostic workup. Even thoughphysicians and the medical literature arc now starting to acknowledgetestosterone in practical terms, it is rarely considered when a man isbeing treated for erectile dysfunction. Even though disturbances inthese hormonal systems will significantly impact erectile function, theyare generally ignored when erectile dysfunction is assessed and treated.In summary, the understanding of erectile dysfunction is very imprecisein modern medical practice.

There is currently no standardized method of diagnosis or treatment thatbegins to address the many normal causes of ED. The diagnosis oferectile dysfunction generally relies on self-reporting by patients.Since the majority of men experiencing significant erectile dysfunctionwill not be aware that they are having erectile dysfunction they willnot report any concerns to their physician. Even when they are givenmedical therapies that worsen their erectile function, for example, manycommon prescription medications, such as anti-hypertensives will worsenerectile function while other medications may improve their erectilefunction, they will be unaware of these changes. It is the experience ofthe inventor that patients and physicians tend to recognize only moreprofound levels of erectile dysfunction and most cases of declining orimproving erectile function go unrecognized.

Histologically there are specific changes that have been well documentedin the penis of men with erectile dysfunction that tend to increase withage. Men who experience declining erectile function have actual physicalchanges within their penis.

Some of these changes include reduced smooth muscle, reduced diameterand size of the cavernosal nerves, reduced levels of elastin andincreased levels of collagen all of which result in impaired vascularresponse, reduced relaxation of the cavernosal sinuses and impairment ofthe veno-occlusive mechanism to properly pressurize the cavernosalsystem. None of the current therapies for erectile function address orare known to treat or improve these physical changes.

All of the current medications being used to treat erectile dysfunctionwork by directly or indirectly causing smooth muscle relaxation in theerectile tissue. This results in dilation of the arteries bringing bloodinto the erectile tissue and dilation of the cavernosal sinuses. Theseeffects are transient, from minutes to several hours and they can onlybe effective while they are present in the penis at therapeutic levels,and this would include oral agents (phosphodiesterase-5 inhibitors, suchas Levitra™, Viagra™, and Cialis™, dopamine agonists, such as Uprima™,and alpha-receptor blocking drugs), intracavernosally injectedvasodilators (papaverine, phentolamine, prostaglandin E1, vasoactiveintestinal peptide), transurethral vasoactive agents (prostaglandin E1,sometimes marketed as MUSE™), vacuum erection devices, and vascularsurgery. Rings work by reducing venous out flow relative to inflow.Penile prostheses simply replace the erectile tissue with a rigid orsemi-rigid structure. Each of these options has its own disadvantages.However, all of the current medications do not reverse or improve thephysical changes causing erectile dysfunction, hence, they have noability to cure erectile dysfunction. They can be effective while thesemedications are present at therapeutic levels in the tissues where theydirectly exert their effects.

Current pharmacological treatments for erectile function such asphosphodiesterase 5-blockers and intracavernosally administeredmedications, such as the vasodilator PGE1 alpha improve erectileresponses by transiently producing elevated levels of blood flow andincreased dilation of the cavernosal tissue to allow the arterial inflowto sufficiently pressurize the erectile tissue and activate theveno-occlusive system tissue to produce a usable erection.

It is known that men who consistently under all circumstances fail torespond with functional erections to maximal pharmacotherapy with oralor intracavernosal medications have to resort to using a pump and a verytight penile ring or undergo the surgical insertion of an implant.Frequent prolonged use of pumps and rings will damage the penis, andsurgery results in an immediate irreversible destruction of the erectiletissues.

Histologically, there are specific changes that are associated witherectile dysfunction. These histological changes are:

1. increase in the percentage of collagen relative to smooth muscle inthe cavernosal tissues;

2. decrease in the percentage of smooth muscle relative to collagen inthe cavernosal tissues;

3. reduced elastin;

4. decreased cavernosal arterial inflow;

5. decreased cavernosal expansion during sexual stimulation; and

6. increased level of sexual stimulation needed to achieve and maintaina functional erection.

There is, therefore, a need for a safe, effective treatment that wouldinduce long lasting physical changes in the penis that would allow aman's penis to be functional without the need to take a pill or injectmedication into the penis every time he wants to be sexually active, andthat could actually induce long lasting physical changes in the penisthat would improve erectile function after medication had beendiscontinued.

SUMMARY OF THE INVENTION

The inventor has discovered that the local application of low doses ofhormones of use according to the invention at 10 to 4000 times less thanthe systemic doses that would be used to treat medical conditionsunrelated to erectile dysfunction can effectively treat erectiledysfunction and induce physical changes to improve erectile function.

Somatomedin-c (IGF1, Mecasermin, CEP-151, FK-780, Insulin-like growthfactor 1, rhIGF1, Mescarina, Mescarmine, Mescarmina Rinfabate) or IrIGF1 or Long IGF1-1r3 or any other functional agonist of the IGF1receptor (or its functional equivalent) herein termed “SC”, is anInsulin like Growth factor that is stimulated to be produced mainly inthe liver and other sites in the body that can respond to Human GrowthHormone. In the practise of the present invention, it has been used atdoses starting doses of 40-80 μg/kg twice daily which would be 6,000 to12,000 μg/day or 42,000 to 84,000 for a 75 kg male, and to a maximum of120 μg/kg twice daily which would be 18,000 μg/day or 126,000 g/week.The inventor has found that men injecting Somatomedin-C in doses as lowas 50-100 μg/once per week into a single or multiple sitessub-cutaneously or even subdermally in the penis obtained a dramaticimprovement in their erectile function. A dose of 50 μg per week is1/2500 of the recommended maximum systemic dose for a 75 kg male.Alternatively, men who were regularly using intracavernosal injectionsto function sexually could just add 10-50 μg of IGF1to their routineintracavernosal injections.

Further, the inventor has found that men who were locally injecting 6-12units/week of long IGF1-1r3 (also called 1r-IGF1 by some manufacturers)seemed to be roughly equivalent to the Somatomedin-C dose of 50-100μg/once per week into a single or multiple sites sub-cutaneously or evensubdermally in the penis had a dramatic improvement in their erectilefunction. Alternatively, men who were regularly using intracavernosalinjections could inject IGF-1 alone or alternatively add a dose of 2-6μg of long IGFI-1r3 into their usual dose of intracavernosal medicationto reduce the number of injections into the penis. A dose of 2-6 μg oflong IGF1-1r3 seemed to be equivalent to 10-50 μg Somatomedin-C (IGF1)dose being premixed or simply added at the time the syringe was loadedfrom a multi-dose sterile bottle to their routine intracavernosalinjections.

Even local subdermal, subcutaneous or deeper injections at doses ofIGF1-1r3 as low as 0.5-2 μg applied daily or 5-20 μg applied weekly, orequivalent dose or other IGFI receptor agonist, gave a clinicalresponse. Men who had used the higher locally applied penile doseslisted above and who relied on PDE5's to treat their ED started to getfunctional erections without the need for PDE5's within 1-2 weeks andthe improvement in erectile function continued beyond 6 weeks. In fact,the longer they used this IGF1 treatment the easier it became to achievea spontaneous erection without any medication. The longer they used thetreatment, the longer the effects lasted upon discontinuation. Men whohad used only a couple of doses of IGF1 found the functional improvementthat occurred noticeably started weakening after 1-2 weeks and wasessentially gone after a month. However, men who had used the treatmentfor longer periods noticeably took longer before they felt theirerectile function was declining, and some men found the benefits of thistreatment lingered for several months after the treatment stopped.

It should be noted that higher doses injected at the frequencies listedabove were more effective. The effectiveness of these therapies can beincreased with lower doses applied more frequently to the penis,although the use of multiple injections may not be tolerated as well.For comfort, the finest commercially available needles are preferred,such as, for example, 30 or 31 gauge. Further, a small implantable formof mechanical device or pellet planted under the skin or otherexternally applied device to produce a sustained slow continuous orpulsed release of a biologically active of IGF1 receptor agonist with orwithout androgen also tended to improve bioavailability while reducingthe total dose of these hormones that are delivered to the tissues ofthe penis.

When IGF's such as IGF-1 (Somatomedin-C) and analogue LR3 IGF1,androgens, vasodilators, or type 5 phosphodiesterase inhibitors arelocally applied, they cannot exert any physiological effect on distanttissues until they have been transported to these distant tissues. Theprocess dispersion and transportation will result in concentrations inthese distant sites that are multiple magnitudes of order lower than thelevels present originally in the penis.

The positive effects of the IGF-1 receptor agonists, e.g. IGF-1(Somatomedin-C; analogue LR3 IGF1) when combined with androgens onerectile function have also been observed by the inventor to be almostentirely local. The inventor discovered that when small systemic dosesof IGF's or IGF's and androgens are applied to a male that have nodetectable response when applied systemically, i.e. doses that would betoo low to raise the systemic levels or physiologic levels of thesehormones in the serum when administered systemically, the same dose whenapplied locally to the penis and genital structures causes a dramaticimprovement in erectile function. For example, doses of IGF1 receptoragonist and androgens that are 1/10 to 1/2500 of the minimum systemicdose necessary for a male to report an improvement in their erectilefunction, when this same dose of IGF's or IGF's and androgen are appliedlocally to the penis, they have a dramatically stronger effect than themuch larger systemic dose applied systemically. A male will observedramatically harder and firmer erection when stimulated. On thecontrary, if these locally effective doses of 1/10-1/2500 of aneffective systemic dose are then applied systemically outside the penis,the positive benefits observed from local an application will disappear.

In a preferred aspect, IGF's and androgens are applied locally at verylow doses to yield optimal erectile function due to their local actionin the penis while minimizing side-effects.

As a result of the small volume of the penis relative to the rest of thebody, small systemic doses have profound effects when applied directlyto the penis. This is accompanied by dramatically lower systemic levelsand significantly lower risks of systemic side effects. Effective localapplication of low dose IGF-1 receptor agonists will eliminate orsignificantly diminish the known side effects of long termadministration of IGF1 receptor agonist such as organomegaly,enlargement of hands, feet and other hard and soft tissues of the body.As stated hereinabove, generally, doses 1/500 to 1/2500 of the systemicdose can be applied locally for good effect.

It is possible to locally apply to the penis doses greater than 1/10 ofthe systemic dose, but these higher doses would (1) produce tissuelevels in the penis where the dose response curve was flat and wherehigh concentrations would yield minimal benefit due to saturation ofreceptors; (2) cause physiologic or supra-physiologic levels outside ofthe penis which would also be beneficial but these higher levels wouldclearly be associated with much higher risks of negative or unwantedside effects both locally in the penis and systemically.

Conversely doses below 1/2500 of the systemic dose will also bebeneficial, but the positive effects are not as robust and much moresubtle to detect clinically.

Clearly, even if local doses were applied systemically, which wouldgenerally be 1/500 to 1/2500 of the maximal safe systemic dose areadministered systemically of IGF's (IGF-1 (Somatomedin-C) and analogueLR3 IGF1) alone, of IGF's (IGF-1 (Somatomedin-C) and analogue LR3 IGF1)and androgens, IGF's (IGF-1 (Somatomedin-C) and analogue LR3 IGF1) incombination with locally applied vasodilators, of IGF's

(IGF-1 (Somatomedin-C) and analogue LR3 IGF1) combined with PDE's, andwith IGF's (IGF-1 (Somatomedin-C) and analogue LR3 IGF1) and androgenscombined with vasodilators or PDE's, it will be difficult to clinicallyobserve a clear beneficial effects on erectile function. Once again,when a small systemic dose is applied outside the penis, it will bediluted thousands of times as it disperses systemically before it can betransported by the circulatory system to the penis, compared to the hightissue levels achieved by a local application into the penis.

To be effective, systemic applications require dramatically largerdoses, and the risks of toxicity and safety will limit the beneficialeffects of systemic applications of these medications (IGF's, androgens,vasodilators, phosphodi-esterase inhibitors) relative to the lower localdoses recommended in this invention. In most cases it has beendiscovered by the inventor that the largest safe systemic doses cannotachieve the same benefit to erectile function on the penis as a muchsmaller and much safer locally applied dose of these medications.

In one aspect, the invention provides a pharmaceutical composition forenhancing male erectile function comprising an erectilefunction—enhancing amount of an insulin-like growth factor 1 agonistselected from the group consisting of IGF-1 (Somatomedin-C) and analogueLR3 IGF1 in admixture with a pharmaceutically-acceptable diluent orcarrier.

In a further aspect, the invention provides a method of enhancing maleerectile function comprising administering to a male a compositioncomprising an erectile function-enhancing amount of an insulin-linegrowth factor selected from the group consisting of IGF-1(Somatomedin-C) and analogue LR3 IGF1 in admixture with apharmaceutically-acceptable diluent or carrier.

In a further aspect, the invention provides a use of a compositioncomprising an effective amount of insulin-like growth factor selectedfrom the group consisting of IGF-1 (Somatomedin-C) and analogue LR3 1GF1 and a pharmaceutically-acceptable carrier or diluents for enhancingmale erectile function.

In a further aspect, the invention provides a method of manufacturing amedicament intended for the application of enhancing male erectilefunction characterized in that insulin-like growth factor (IGF) selectedfrom IGF-1 (Somatomedin-C) and LR3 IGF1 is admixed with apharmaceutically-acceptable carrier.

The present invention provides for methods, compositions, uses and kitsfor the enhancement of male erectile function, which involves theadministration of an insulin-like growth factor.

Preferably, the IGF is Somatomedin-c (IGF1, Mecasermin, CEP-151, FK-780,Insulin-like growth factor 1, rhIGF1, Mescarina, Mescarmine, MescarminaRinfabate) or 1r IGF1 or Long IGF1-1r3 or any other functional agonistof the IGF1 receptor (or its functional equivalent).

IGF-I (Somatomedin-C) comprises a full length protein of 70 amino acidsin a single chain with three intramolecular disulfide bridges. Examplesof recombinant human IGF-I and recombinant LR3 IGF-I are products madeby GroPep Ltd. (Adelaide, Australia) and other commercial laboratories.

Preferably, the invention provides a use as hereinabove defined whereinsaid composition further comprises an androgen.

Preferred androgens to be combined with an insulin-like growth factor 1receptor agonist are selected from testosterone, or dihydrotestosterone,or testosterone and dihydrotestosterome or pharmaceutically-acceptableesters of testosterone and dihydrotestosterone,pharmaceutically-acceptable derivatives of testosterone such as methyltestosterone, testolactone, oxymetholone and fluoxymesterone.Testosterone and testosterone esters, such as testosterone enanthate,testosterone propionate and testosterone cypionate, may be used. Theaforementioned testosterone esters are commercially available or may bereadily prepared using techniques known to those skilled in the art ordescribed in the pertinent literature.

In a further use as hereinabove defined the compositions of LR3 IGF-I orIGF1 further comprise a vasodilator. Preferably, the vasodilator isselected from the group consisting of papaverine, chlorpromazine,atropine, phentolamine, a prostoglandin and mixtures thereof.

In a further use as hereinabove defined the compositions of LR3 IGF-I orIGF1 further comprises an androgen and a vasodilator.

Preferably, in further embodiments the compositions further comprise aprostaglandin, preferably prostoglandin E1.

Preferably, use of the compositions in the practice of the inventioncomprises applying the composition locally to the penisintracavernosally at a dose selected from 0.1 to 100 μg.

Preferably, the male is a man.

In a preferred practice of the invention, the IGF-I compositions of LR3IGF-I or IGF1 of use according to the invention are administered, forexample, by subcutaneous injection, high pressure jet device,intracavernous injection, intravenous injection, small implantablemechanical device, small pellet, externally applied pump and syringe,intramuscular injection, intradermal injection, intra-nasal or topicaladministration while the vasodilator is delivered only byintracavernosal injection.

The male erectile dysfunction to be treated or prevented is, mostgenerally, erectile dysfunction from all causes, both primary andinduced by known and unknown secondary causes of erectile dysfunctionsuch as hereinbefore described including but not limited to hormonalimbalances, nutritional imbalance, pharmaceutically induced, prolongedstress and psychological causes, to nerve dysfunction, arterialinsufficiency, venous leakage, severe vascular insufficiency, mildvascular disease, hormonal insufficiency, drug use, surgery,chemotherapy, or radiation.

Small locally applied doses of IGF-1 (Somatomedin-C) and analogue LR3IGF1 which produce low systemic doses will in turn eliminate or reduceand systemic effects and systemic side effects while producing verysignificant improvement in erectile function. For example, a male mayhave to take 50-150 mcg of IGF-1 (Somatomedin-C) or analogue LR3 IGFI ona daily basis systemically to effect the same improvement in erectilefunction as 2 -5 mg of IGF-1 (Somatomedin-C) or analogue LR3 IGF1applied locally to the penis. And if the same male applied 2-5 mcg ofIGF-1 (Somatomedin-C) or analogue LR3 IGFI systemically at a siteoutside of the genital area he would observe no improvement in hiserectile function.

In a further aspect, the IGF-I composition comprising LR3 IGF-I or IGF1is administered locally to the penis in combination with preferably anandrogen such as testosterone and dihydrotestosterone administered bysubcutaneous injection, high pressure jet device, intracavernosalinjection, intravenous injection, intramuscular injection, intradermalinjection, intra-nasal or topical administration, internal micropump orslow release technology, or external pump.

In a further aspect, the invention provides use of a composition for themanufacture of a medicament for treating male erectile dysfunction in amammal characterized in that said composition comprises an insulin-likegrowth factor (Somatomedin-c (IGF1, Mecasermin, CEP-151, FK-780,Insulin-like growth factor 1, rhIGF1, Mescarina, Mescarmine, MescarminaRinfabate) or Ir IGF1 or Long IGF1-1r3 or any other functional agonistof the IGF1 receptor (or its functional equivalent) as hereinbeforedefined.

In a preferred aspect, the invention provides a use as hereinabovedefined wherein said IGF is LR3 IGF-I, or IGF-I (Somatomedin-C).

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises an androgen injected withandrogen.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition for the injectable mixture further comprises avasodilator.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises an androgen and avasodilator.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises a PDE5 inhibitor.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises an androgen and a PDE5inhibitor.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises an androgen, PDE5 inhibitorand a vasodilator.

In a further aspect, the invention provides a use as hereinabove definedwherein said composition further comprises a prostaglandin.

In a further aspect, the invention provides a method for manufacturing amedicament intended for the application of treating male erectiledysfunction characterized in that insulin-like growth factor (IGF-1Somatomedin-c (IGF1, Mecasermin, CEP-151, FK-780, Insulin-like growthfactor 1, rhIGF1, Mescarina, Mescarmine, Mescarmina Rinfabate) or 1rIGF1 or Long IGF1-1r3 or any other functional agonist of the IGF1receptor (or its functional equivalent) is admixed with apharmaceutically-acceptable carrier.

In a further aspect, the invention provides for a kit comprising theabove-described combinations and an instruction for using thecombination in treating, improving, curing or preventing male erectiledysfunction.

As used herein, “enhanced erectile function” refers to the ability toachieve and maintain a penile erection adequate for sexual intercoursemore often than the man was able to before the treatment presented inthe instant application. Indications that this treatment is effectiveinclude the decreased or eliminated reliance on medications and/orimproved response to the medications currently used to treat erectiledysfunction or aid in achieving an adequate erection, more frequentspontaneous erections, an improved ability to sustain an erection beforeand after ejaculation, a reduction in the absolute and relativerefractory period after ejaculation before another erection can beachieved, a reduced requirement for stimulation to achieve and maintainan erection and an increase in frequency, firmness and duration ofmorning erections and an increase in frequency, firmness and duration ofspontaneous erections. Any of these indicators, alone or in combination,can be used as a measure of effectiveness.

Administration to the cavernosal tissue encompasses injections directlyinto the cavemosal tissue, which is preferred for men who havepreviously been trained on the proper method for intracavernosalinjections and are currently using intracavernosal injections. For menwho are not skilled with IC injections, the preferred injection would beinjections to the connective tissues, which surround the cavernosaltissue from where the active agents of the present invention, in awater-based or oil-based system, will diffuse into the cavernosaltissue. Through this route, generally less of the administered dosewould be delivered to the cavernosal tissue than if it were injecteddirectly into the cavernosal tissue. Other routes of administrationconsidered to be administration to the cavernosal tissue includeurethral suppositories, implantable sustained-release drugs or devices,and transdermal devices or vehicles which are directly in contact withor adhered to the penis, such as patches, creams, or lotions.Optionally, the transdermal devices or vehicles may be delivered by acondom-like device.

In preferred embodiments of the invention the pharmaceuticalcompositions are administered to the penile and cavernosal tissue of thepenis of a male patient.

The pharmaceutical composition is administered to the patient in apharmaceutically acceptable sterile dosage form to the tissues of thepenis, which includes the cavernosal tissue. The composition may beadministered topically by transdermal vehicles or devices, such ascreams, lotions, or patches. The composition may be administered byurethral suppository, or parenterally using a needle, auto-injector,slow sustained injection pump, high pressure jet injection device,microinfusion pump, or implantable sustained release drug or device.Sterile dosage forms include, but are not limited to, syringes andneedles, urethral suppositories, or transurethral implants, ampoules orvials, or transdermal vehicles or devices, such as creams, lotions orpatches.

The active ingredient can also be delivered to the penile and cavernosaltissue transdermally. A suitable delivery vehicle or device is situatedin direct contact with the skin of the penis to effect delivery of theagent to the penile and cavemosal tissue. The vehicle or device mayinclude agents which enhance the transdermal absorption rate or agentswhich aid in the absorption of the pharmaceutical composition into thecavernosal tissue.

A particularly preferred transdermal device of the present invention isa patch. A patch is designed to adhere to or be brought into contactwith the skin of the penis so that the pharmaceutical compositioncontained by the patch can be absorbed transdermally and into the penileand cavernosal tissue. The patch may also contain agents which enhance,control. or a combination of both, the transdermal absorption of thepharmaceutical composition and/or the absorption of the pharmaceuticalcomposition into the penile and cavernosal tissue. Optionally, theseagents can be applied in conjunction with the pharmaceuticalcomposition, at a different time, and/or a different route ofadministration. The patch may also include adhesives specially designedto adhere to the often sensitive skin of the penis.

Kits comprising pharmaceutical compositions of the invention formulatedin sterile unit dosage forms suitable for administration to the peniletissue, includes instructions for use in written, oral, videotape,compact disc, other digital electronic form, or other recorded media,are contemplated. Conveniently, a kit wherein the sterile unit dosageforms are for oil based depot injections and instructions for use isprovided.

Usual systemic doses for testosterone may range from around 0.5 to 160mg/day depending on the route of administration and the reason fortreatment.

The appropriate dosage and frequency of treatment may vary dependingupon desire or need of the degree of enhanced erectile function sought.Other health related factors would also be considered. Men without needof great enhancement of their erectile function may not need maximaltreatment. The androgen dosage can be in the range of 0.01 to 100mg/day, more preferably the dosage is in the range of 0.1 to 20 mg/dayof testosterone, or equivalent dose of DHT or other androgen, androgenreceptor agonist, or molecule which binds to an androgen receptor,depending on the route of administration.

The frequency of administration may be in the range of two to threetimes a day for intercavernosal injection, more preferably from 3 to 7times a week, or as infrequently as monthly for delayed releaseformulations or topical administrations. The patient's condition shouldbe monitored and the dosage adjusted, usually titrated upward, ifenhanced erectile function is not achieved. Enhancement in erectilefunction may start immediately, but the major therapeutic effect may beexpected to be achieved within 2 weeks to 6 months, more often within 4weeks to 3 months. This may be followed by a maintenance phase duringwhich there are intermittent or less frequent administrations. This mayinvolve administrations of at least quarterly, bimonthly, biweekly,weekly injections, depending on the route of administration.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In order that the invention may be better understood, preferredembodiments will now be described by way of example only with referenceto the following Examples.

Example 1 Patient A

A 30 year old patient was using intracavernosal injections to effect anerectile response by routinely applying 1.5 ug of prostaglandin E1intracavernosally to the penis. This treatment normally caused a partialerection (70-75% firmness) for about one hour.

It was found that administration by injection of 20 ug of LR3IGF-I inaddition to the prostaglandin EI caused a dramatic increase in thefirmness and duration of the patient's erectile response to effect apriapism, i.e. a 100% erection that did not soften with Pseudophed 180mg and vigorous exercises. Patient also noted that immediately after 20ug of LR3 IGF-1 taken alone without the prostaglandin E1 gave improvederectile function.

Example 2 Patient B

A 51 year old patient routinely applied 6 ug prostaglandin EIintracavernosally to the penis. He was only able to obtain a partialerection (60% firmness) for about 30 mins as a result of venous leakage.Without medication he could not achieve a natural erection stronger than50%.

The patient then started adding 3 ug LR3 IGF-I to the 6 ug prostaglandinEI and when injected the first time it caused an 80-90% erection lastingabout 1 hour.

Over a two week period, the patient carried out several more injectionsof 3 ug of LR3 IGF-I to his 6 ug of prostaglandin E1 and during thistime reported that the firmness of his erections were up to 100% infirmness while the duration increased to up to 2 hours. In addition, thepatient's erectile function increased during this period and he begangetting firm spontaneous erections without the need for medications.

Patient B stopped using LR3 IGF-I and within 2 weeks, he began to noticea gradual decline of erectile function. After two years the patientcontinued to episodically use LR3 IGF-I.

The patient continued to have good erections until he began to developclinical hypothyroidism which ensued after several months of severeradicular neuralgic pain following an injury. As a result of chronicpain and clinical hypothyroidism, the patient's erectile dysfunction haddeclined and he was now not obtaining firm erections when even up to6-10 mcg of LR3 IGF1 was being added to the PGE1 injections and PDE5's.

But when 10 mg of Testosterone was added to the IC mixture of 6 mcg ofLR3 IGF1 plus 6 mcg of PGE1 the patient once again started to obtaindramatically harder and firmer erections. These injections were beingused 2-3 times per week, and the patient began to experience a dramaticreturn of erectile function. After about a month the patient was able tohave sexual intercourse without any medications.

Example 3 Patient C

Patient C was a 48 year old man who had been experiencing severeerectile dysfunction for over 5 years. Patient C originally was nothaving any erections even with maximal doses of Viagras®, Cialis® orLevitra®. He was also unable to obtain a usable erection even withmaximum doses of PGE1 40 ug/ml plus a triple mix with papavarine,atropine and phentolamine.

Patient C was then given some 1% testosterone gel that he was to applytwice daily to his penis. After a few weeks on the topical testosteronethe patient and was able to obtain some usable responses to 80-100 unitsof PGE1 40 ug/ml combined with a triple mix of papavarine, atropine andphentolamine. But even though he was now getting usable erections withhigh doses of intracavernosal injections, he still could not functionwith maximal doses of the PDE5: Viagra®, Cialis® and Levitra®. Whenusing these oral agents with daily topical androgens the patient wasstill not able to achieve useable responses with these oral agents.

Finally when the patient began injecting 10 ug to 20 ug of IGF-I or 6-10ug of LR3 IGF1 sub-cutaneously plus applying the topical 1% testosteronegel into his penis at a frequency of 3-4 times per week for a period ofone month his erections dramatically improved. This combination of IGF'splus androgens plus intracavernosal vasodilators resulted in a dramaticimprovement in erectile function. Patient C was now getting firmerections with only 20-40 units of his intracavernosal meds, and he wasnow obtaining firm usable erections with the PDE5's on the days he didnot use his intracavernosal medications combined with IGF's.

The patient continued to use IGF injections, but ran out of his topicaltestosterone, and after about two weeks without his topical agent, hebegan to find the PDE'5s were no longer working.

The patient was then given some Deletestryl™ 200 mg/ml of testosteroneand was mixing 7 units of testosterone with 10 ug of LR3IGF1. He wasinjecting this intracavernosally and immediately saw his erectilefunction improve again, such that he was once again able to get andsustain usable erections and perform successful intercourse.

Example 4 Patient D

A 62 year old man with long standing erectile dysfunction began seeingan anti-aging physician. His erectile dysfunction was not responding tothe oral medications of Viagra®, Cialis®, or Levitra® and had been onintracavernosal injections for years.

He did not report a significant improvement in his erectile functionsince starting on Growth Hormone injections daily. After 1 year onGrowth Hormones, he began to inject IGF1 subcutaneously in his abdomenat a dose of 50-100 ug/day.

While on systemic doses of 50-100 ug of IGF1 but prior to starting toadd the IGF1 directly into the penis or to combine it with hisintracavernosal injections, the patient was not getting adequateerections when using his intracavernosal meds. Before applying the IGF1locally to the penis the patient found that even if he combined maximaloral doses of Viagra®, Cialis®, or Levitra® with his intracavernosalinjections he was frequently going soft during intercourse.

After several months on the IFG1 injections into the abdominal area, hestarted to intermittently apply some of these daily injections of IGF1into his penis. The patient immediately experienced improved erectilefunction and had to reduce the strength of his erectile dysfunctionmedications because the erections were lasting too long.

After about three months of intermittently applying some of his 50-100ug daily IGF1 injections subcutaneously into the penis the patientstopped these subcutaneous injections into the penis and instead thepatient began to also combine 5-10 ug of IGF1 with his intracavernosalinjections and he reduced his daily dose of IGF1 to 50 ug injected intothe abdomen. After starting the penile and intracavernosal injections ofIGF1 locally into the penis the patient had to reduce hisintracavernosal dose by over 50% because the erections were staying hardtoo long at his old dose and sometimes he would use oral medicationsinstead of injections because he was now getting usable erections withViagra® or Levitra® or Cialis® without the need for intracavernosalinjections.

Finally this patient was diagnosed with low serum testosterone and hewas started on topical 1% Testosterone gel. On starting this treatmenthe noticed an even better level of erectile function, so that hisspontaneous and morning erections had become firmer and more frequent,and his erection with IC Meds and oral PDE5's had improved. He was alsonow starting to get longer-lasting and firmer spontaneous erections evenwithout any medications, and he also had to cut down the dose of hisintracavernosal medicament since starting the local application oftreatment to avoid getting priapisms.

Example 5 Patient E

An 81 year old patient was using intracavernosal injection for over 12years. Initially, with maximal strength intracavernosal injections, thepatient able to penetrate and maintain a usable erection. But hiserectile function continued to decline and for the past couple of yearshe was unable to function. Even when he combined maximal strengthintracavernosal injections with a ring his erections were less than 50%.This patient had no spontaneous erections and he had not had morningerects for over ten years.

The patient started applying 0.2 ml of 2.5% testosterone cream to thehead and shaft of his penis twice daily and after a few months he wasnow getting 70-75% erections which were often going soft afterpenetration.

While continuing to apply the 0.2 ml of 2.5% testosterone cream to thehead and shaft of his penis twice daily, the patient also received foursubcutaneous injections of Mug of IGF1 into the shaft of his penis thatwere injected at intervals of seven days.

The combination of daily topical testosterone being applied to the penisand the four weekly applications of IGF1 injected directly into thepenis dramatically improved the patient's erectile function such that hewas now getting dramatically harder erections under all circumstances.

The application of these medications directly into the penis caused himto start getting regular morning erections and spontaneous erections.The patient could get firm erections with masturbation which had nothappened for many years and his erections after an intracavernosalinjection were now lasting over 40 minutes at over 80% hardness. Theseimprovements persisted for several weeks after the last IGFI injectionand the fact that these improvements continued long after the medicationhad been cleared from the body clearly demonstrates that they hadinduced actual long standing physical changes in the patient's penis.

Example 6 Patient F

A 37 year old patient with erectile dysfunction was using Cialis on aprn basis to treat his erectile dysfunction. The patient applied 2 ug of1r3 IGF1 subcutaneously to his penis three times per week for one month.

By the second local application of 1r3 IGF1 into the patient's penis, hebegan experiencing firmer spontaneous erections and by the third week hewas no longer dependant on Cialis.

When seen three months after stopping the 1r3 IGF1 injections thepatient was continuing to be sexually active without Cialis. Theseimprovements in erectile function persisted for several weeks after thelast IGF1 injection. The fact that these improvements continued longafter the 1r3 IGF1 had been cleared from the body clearly demonstratesthat it had induced long standing physical changes in the patient'spenis.

Example 7 Patient G

This 55 year old male patient had been having erectile dysfunction forover three years. He was not able function sexually with Viagra, Levitraor Ciaslis. He had never used intracavernosal injections to treat hiserectile dysfunction.

In an attempt to improve his erectile function the patient had beenapplying 0.2 grams of 2% Dihydrotestosterone cream to his penis for oversix months with only a slight improvement. With the 0.2 grams of 2%Dihydrotestosterone cream his spontaneous erections with his wife weregetting harder initially but once he penetrated his erections were stillgoing soft well before he could achieve an orgasm.

The patient then received twice weekly subcutaneous injections of 25 ugof IGF1 into the shaft of his penis. The patient immediately beganexperiencing firmer spontaneous erections and was now easily getting andsustaining firm erections through to orgasm and ejaculation. When seenover several months the patient improvements in erectile function wouldpersist for several weeks after the last IGF1 injection. But the patientwas needing to inject 25 ug of IGF1 into the shaft of his penis once ortwice per month to maintain optimal erections.

The fact that these improvements continued weeks after the IGF1 had beencleared from the penis and the body clearly demonstrates thatDihydrotestosterone and IGF1 had induced long standing physical changesin the patient's penis.

Although this disclosure has described and illustrated certain preferredembodiments of the invention, it is to be understood that the inventionis not restricted to those particular embodiments. Rather, the inventionincludes all embodiments which are functional or mechanical equivalenceof the specific embodiments and features that have been described andillustrated.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A pharmaceuticalcomposition for enhancing male erectile function comprising an erectilefunction—enhancing amount of insulin-like growth factor IGF-1 receptoragonist (SC) in admixture with a pharmaceutically-acceptable diluent orcarrier.
 2. A composition as claimed in claim 1 comprising an androgen.3. A composition as claimed in claim 2 wherein said androgen is selectedfrom testosterone, dihydrotestosterone and a mixture thereof.
 4. Acomposition as claimed in any one of claims 1 to 3 comprising avasodilator.
 5. A composition as claimed in any one of claims 1 to 4comprising PDE5 inhibitor.
 6. A composition as claimed in claim 4 orclaim 5 wherein said vasodilator is selected from papaverine,chlorpromazine, atropine, phentolamine, a prostaglandin or mixturesthereof.
 7. A composition as claimed in claim 6 wherein saidprostaglandin is prostaglandin E1.
 8. A method of enhancing maleerectile function comprising administering to a male a compositioncomprising an erectile function-enhancing amount of an insulin-likegrowth factor selected from the group consisting of IGF-1(Somatomedin-C) and analogue LR3 IGF1 in admixture with apharmaceutically-acceptable diluents or carrier.
 9. A method as claimedin claim 8 wherein said composition comprises an androgen.
 10. A methodas claimed in claim 8 or claim 9 wherein said composition comprises avasodilator.
 11. A method as claimed in claim 10 wherein saidvasodilator is selected from papaverine, chlorpromazine, atropine,phentolamine, a prostaglandin and mixtures thereof.
 12. A method asclaimed in any one of claims 9 to 11 comprising PDE5 inhibitor.
 13. Amethod of enhancing male erectile function comprising (a) administeringto a male a composition comprising an erectile function-enhancing amountof an insulin-like growth factor selected from the group consisting ofIGF-1 (Somatomedin-C) and analogue LR3 IGF1 in admixture with apharmaceutically-acceptable diluents or carrier and (b) administering acomposition comprising an androgen.
 14. A method as claimed in claim 13wherein said androgen is testosterone or dihydrotestosterone.
 15. Amethod of enhancing male erectile function comprising (a) administeringto a male a composition comprising an erectile function-enhancing amountof an insulin-like growth factor selected from the group consisting ofIGF-1 (Somatomedin-C) and analogue LR3 IGF1 in admixture with apharmaceutically-acceptable diluents or carrier and (b) administering anenhancing amount of a composition comprising a vasodilator.
 16. A methodas claimed in claim 15 wherein said vasodilator is selected frompapaverine, chlorpromazine, atropine, phentolamine, a prostaglandin ormixtures thereof.
 17. A method as claimed in claim 16 wherein saidprostoglandin is prostaglandin E1.
 18. A use of a composition comprisingan effective amount of insulin-like growth factor selected from thegroup consisting of IGF-1 (Somatomedin-C) and analogue LR3 1GF1 and apharmaceutically-acceptable carrier or diluents for enhancing maleerectile function.
 19. A use as claimed in claim 18 wherein saidcomposition comprises an androgen.
 20. A use as claimed in claim 19wherein said androgen is selected from testosterone, dihydrotestosteroneand mixtures thereof.
 21. A use as claimed in claim 18 or claim 19wherein said composition comprises a vasodilator.
 22. A use as claimedin claim 21 wherein said vasodilator is selected from papaverine,chlorpromazine, atropine, phentolamine, a prostaglandin or mixturesthereof.
 23. A use as claimed in any one of claims 18 to 22 wherein saidcomposition comprises PDE5 inhibitor.
 24. A method of manufacturing amedicament intended for the application of enhancing male erectilefunction characterized in that insulin-like growth factor (IGF) selectedfrom IGF-1 (Somatomedin-C) and LR3 IGF1 is admixed with apharmaceutically-acceptable carrier.
 25. A method as claimed in claim 24further comprising admixing said IGF with an androgen.
 26. A method asclaimed in claim 24 or claim 25 wherein said IGF is admixed with avasodilator.
 27. A method as claimed in claim 26 wherein saidvasodilator is selected from papaverine, chlorpromazine, atropine,phentolamine, a prostaglandin or mixtures thereof.
 28. A method asclaimed in any one of claims 24 to 27 wherein said IGF is admixed withPDE5 inhibitor.
 29. A method as claimed in any one of claims 8 to 17wherein said administration comprises subcutaneous injection, highpressure jet device, intracavernous injection, intravenous injection,intramuscular injection, intradermal injection, intra-nasal or topicaladministration.
 30. A method as claimed in claim 29 wherein saidadministration is topical administration.